Anti-hepatitis C Daclatasvir synthesis method

A technology of anti-hepatitis C daclatasvir and synthetic method, which is applied in the field of synthesis of anti-hepatitis C daclatasvir, can solve the problems of complex synthetic route and high cost of production raw materials, and achieve simple reaction, low cost of production raw materials, and step-by-step synthetic route little effect

Inactive Publication Date: 2017-02-22
上海步越化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to provide a synthetic method of anti-hepatitis C daclatasvir, which solves the above-mentioned existing problems in the prior art such as high raw material cost and complex synthetic route

Method used

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  • Anti-hepatitis C Daclatasvir synthesis method
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  • Anti-hepatitis C Daclatasvir synthesis method

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preparation example Construction

[0025] Such as Figure 4 Shown, a kind of synthetic method of anti-hepatitis C daclatasvir, this synthetic method comprises the following steps:

[0026] (1) Using 4,4'-bis(2-chloroacetyl)biphenyl to condense with Boc-L-proline to generate ester;

[0027] (2) take above-mentioned ester and ammonium acetate ring closure, obtain imidazole;

[0028] (3) De-Boc the imidazole to obtain the hydrochloride;

[0029] (4) Take the hydrochloride and carry out Moc-L-valine condensation to obtain daclatasvir.

specific Embodiment approach 1

[0031] (1) Synthesis of esters

[0032] Stage a. Put 4,4'-bis(2-chloroacetyl)biphenyl (7.5g, 24.4mmol), Boc-L-proline (10.5g, 48.8mmol) and acetonitrile (70mL) into the reaction flask , add diisopropylethylamine DIPEA (6.5g, 50mmol);

[0033] Stage b. Heat up to 25°C (temperature range is 25-82°C), stir for 36 hours, the reaction is completed, the reaction solution is concentrated under reduced pressure, and replaced with toluene solution (140mL);

[0034] Stage c, washing twice with saturated sodium chloride (70 mL), concentrating toluene to obtain an oily foamy solid, namely the desired ester (15.6 g, yield 96.3%).

[0035] (2) Synthesis of imidazole

[0036] Add ester (15.6g, 23.5mmol) and 95mL toluene to the reaction flask, add ammonium acetate (30g, 389mmol), heat up to 95°C (temperature range is 95-100°C), and react for 15 hours;

[0037] Cool down to 60°C, slowly add saturated aqueous sodium bicarbonate solution, adjust the pH to 7 (PH range 7-8);

[0038] Layer at ...

specific Embodiment approach 2

[0049] (1) Synthesis of esters

[0050] Stage a. Put 4,4'-bis(2-chloroacetyl)biphenyl (7.5g, 24.4mmol), Boc-L-proline (10.5g, 48.8mmol) and acetonitrile (70mL) into the reaction flask , add diisopropylethylamine DIPEA (6.5g, 50mmol);

[0051] Stage b: heat up to 65°C (temperature range is 25-82°C), stir for 8 hours, the reaction is completed, the reaction solution is concentrated under reduced pressure, and replaced with toluene solution (140mL);

[0052] Stage c, washing twice with saturated sodium chloride (70 mL), concentrating toluene to obtain an oily foamy solid, namely the desired ester (15.6 g, yield 96.3%).

[0053] (2) Synthesis of imidazole

[0054] Add ester (15.6g, 23.5mmol) and 95mL toluene to the reaction flask, add ammonium acetate (30g, 389mmol), heat up to 97°C (temperature range is 95-100°C), and react for 15 hours;

[0055] Cool down to 60°C, slowly add saturated aqueous sodium bicarbonate solution, and adjust the pH to 7.3 (pH range 7-8);

[0056] Laye...

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Abstract

The invention discloses an anti-hepatitis C Daclatasvir synthesis method. The anti-hepatitis C Daclatasvir synthesis method comprises the following steps that 1, 4,4'-di(2-chloracetyl) biphenyl and Boc-L-proline perform condensation to generate ester; 2, the ester and ammonium acetate perform ring closure to obtain imidazole; 3, Boc is removed from the imidazole to obtain hydrochloride; 4, the hydrochloride is taken for Moc-L-valine condensation to obtain Daclatasvir, wherein in the step 1, a solvent is acetonitrile, and an acid-binding agent is diisopropylethylamine. By the adoption of the anti-hepatitis C Daclatasvir synthesis method, the preparation raw materials are low in cost, synthetic route steps are few, reaction is simple, and popularization and application are promoted.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a synthesis method of anti-hepatitis C daclatasvir. Background technique [0002] Daclatasvir (DAKLINZA) is a hepatitis C virus (HCV) NS5A inhibitor indicated for use with sofosbuvir for the treatment of chronic HCV genotype 3 infection. Its application has attracted people's attention, thus putting forward higher requirements for the production and synthesis method of daclatasvir. [0003] WO2008021927, WO2009020825, WO2009020828, WO2012048421, US20090068140 and US20100158862 have reported the synthesis method of daclatasvir, so far there are three synthesis methods of the drug. The first method: using p-bromoacetyl bromide as the starting material, first condense with Boc proline, then close the ring with ammonium acetate, and then prepare a boronate ester for coupling, finally remove Boc protection, and combine with Moc- L-valine is condensed to obtain daclatasv...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 周盛峰冯志勇宋斌陈龙
Owner 上海步越化工科技有限公司
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